Small cationic multidrug efflux pump (substrates: cationic lipophilic drugs), EmrE. This pump confers resistance to a wide range of disinfectants and dyes known as quaternary cation compounds (QCCs). The 3-D structure of the dimeric EmrE shows opposite orientation of the two subunits in the membrane (Chen et al., 2007), and this conclusion has been confirmed (Fleishman et al. 2006; Lehner et al. 2008; Lloris-Garcerá et al. 2013). There may be a single intermediate state in which the substrate is occluded and immobile (Basting et al., 2008). Direct interaction between substrates (tetraphenylphosphonium, TPP+ and MTP+) and Glu14 in TMS1 has been demonstrated using solid state NMR (Ong et al. 2013). A Gly90X6Gly97 motif is important for dimer formation (Elbaz et al., 2008). Two models may account for the opposite (inverted) orientations of the two identical subunits. A post-translational model posits that topology remains malleable after synthesis and becomes fixed once the dimer forms. A second, co-translational model, posits that the protein inserts in both topologies in equal proportions (Woodall et al. 2015). Protonation of E14 leads to rotation and tilt of transmembrane helices 1-3 in conjunction with repacking of loops, conformational changes that alter the coordination of the bound substrate and modulate its access to the binding site from the lipid bilayer. The transport model that emerges posits a proton-bound, but occluded, resting state. Substrate binding from the inner leaflet of the bilayer releases the protons and triggers alternating access between inward- and outward-facing conformations of the substrate-loaded transporter, thus enabling antiport without dissipation of the proton gradient (Dastvan et al. 2016). TMS4 is the known dimerization domain of EmrE (Julius et al. 2017). Few conserved residues are essential for drug polyselectivity. Aromatic QCC selection involves a greater portion of conserved residues compared to other QCCs (Saleh et al. 2018). The topologies of helical membrane proteins are generally defined during insertion of the transmembrane
helices, yet topology can change after insertion. In EmrE, topology flipping occurs so that the populations in both orientations equalize. Woodall et al. 2017 demonstrated that when EmrE is forced to insert in a distorted topology, topology
flipping of the first TMS can occur, and
topological malleability also extends to the C-terminal helix; even complete
inversion of the entire EmrE protein can occur after the full protein is translated and inserted.
Thus, topological rearrangements appear to be possible during biogenesis. Subtle but significant differences in the sizes of EmrE with different QCC ligands bound has been reported (Qazi and Turner 2018).

DUF6 homologue, YhbE of 412 aas and 10 TMSs. Encoded by a gene that precedes the Obg GTPase involved in cell division and cell cycle control (Verstraeten et al. 2015). obg is expressed from an operon encoding two ribosomal proteins. The operon's expression varies with growth phase and is
dependent on the transcriptional regulators, ppGpp and DksA (Maouche et al. 2016).

Possible transporter of polar amino acids including glutamate, glutamine and aspartate, DmeA. It complements a sepJ mutation in Anabaena (TC# 2.A.7.23.2), and SepJ complements a dmeA mutation. Alternatively, and less likely, it could be an
activator of an ABC transporter catalyzing uptake of these amino
acids (Escudero et al. 2015).

SepJ, a novel composite protein of 751 aas needed for cellular filament integrity, proper heterocyst development and N2 fixation. It has a C-terminal DME family domain (Flores et al., 2007). Mullineaux et al. (2008) have proposed that this protein (SepJ; FraG) may be a channel-forming protein for transfer of metabolites between cells. However, it may instead be a polar amino acid transporter since DmeA of Synecococcus (TC# 2.A.7.3.58) complements a defect in SepJ (E. Flores, unpubished observations).

SepJ of 751 aas and 10 C-terminal domains with an N-terminal SMC (structural maintenance of chromosomes) domain and a central DUF4775 domain, before the 10 TMS DMT domain. It may transport asp, glu and gln, or it may activate an ABC-type transporter of this specificity (Escudero et al. 2015). It may be a part of the cyanobacterial intercellular septum together with FraC (P46078) and FraD (P46079).

Golgi UDP-galactofuranose transporter, UgtA of 399 aas and 11 TMSs (Engel et al. 2009). This and several other species have two redundant transporters that can substitute for each other, UgtA and UgtB (Park et al. 2015). Plays a role in hyphal morphogenesis, cell wall archtecture, conidiation and drug susceptibility (Engel et al. 2009). This and several other species have two redundant transporters that can substitute for each other, UgtA and UgtB (Park et al. 2015). Plays a role in hyphal morphogenesis, cell wall archtecture, conidiation and drug susceptibility (Afroz et al. 2011).

UDP-galactofuranose transporter of 400 aas and 11 TMSs, GlfB (Engel et al. 2009). Galactofuranose-containing glycolipids and glycoproteins are in the
cell envelopes of several eukaryotes where they have been shown to contribute, for example, to the
virulence of the parasite Leishmania major and the fungus Aspergillus fumigatus.

The triose-P:Pi antiporter, TPT or Ape2 of 410 aas and 10 TMSs. Transports inorganic phosphate,
3-phosphoglycerate (3-PGA), 2-phosphoglycerate (2PG) and phosphoenolpyruvate (PEP) as well as triose phosphates. Functions in the export
of photoassimilates from chloroplasts during the day. In the light,
triose phosphates are exported from the chloroplast stroma in counter
exchange with inorganic phosphate (Pi), generated for sucrose
biosynthesis in the cytosol. Involved in photosynthetic acclimation, a
light response resulting in increased tolerance to high-intensity light (Knappe et al. 2003). The crylstal structures of TPT from Galdieria sulphuraria have been solved revealing the protein bound to two different substrates, 3-phosphoglycerate and inorganic phosphate, in occluded conformations.

The phosphoenolpyruvate/phosphate translocator, pPT, of 524 aas in the outer membranes of apicoplasts, vestigial plastids in apicomplexan parasites such as Plasmodium. Transports glucose-6 P and triose-3 Ps via an inorganic phosphate antiport mechanism. Apicomplexan parasites are dependant on their apicoplasts for synthesis of various
molecules that they are unable to scavenge in sufficient quantity from their host. They import carbon, energy and
reducing power to drive anabolic synthesis in the organelle. pPT is targeted
into the outer apicoplast membrane via a
transmembrane domain that acts as a recessed signal anchor to direct the protein into the
endomembrane system. A tyrosine in the cytosolic N-terminus of the protein is essential for
targeting (Lim et al. 2016).

Endoplasmic reticular multifunctional nucleotide sugar transporter, Efr. Substrates include GDP-fucose which can be used to fucosylate the luminar domain of the transmembrane NOTCH receptor (Ishikawa et al. 2010).

Pig Golgi-resident UDP-N-acetylglucosamine transporter of 325 aas and 10 TMSs with the N- and C-termini in the cytoplasm, SLC35A3. Essential TMSs and residues have been identified (Andersen et al. 2007).

Tobacco nicotine uptake permease 1, NUP1, of 353 aas and 10 TMSs. NUP1 transports tobacco alkaloids such as nicotine, but also efficiently takes up
pyridoxamine, pyridoxine and anatabine. The naturally
occurring (S)-isomer of nicotine was preferentially transported over the
(R)-isomer. NUP1, similar to PUP1 of A. thaiana,
transported various compounds containing a pyridine ring, but the
two transporters had distinct substrate preferences (Kato et al. 2015).

Eukaryota

Viridiplantae

Nup1 of Nicotiana tabacum

2.A.7.15: The UDP-glucuronate/UDP-N-acetylgalactosamine Transporter (UGnT) Family

General amino acid exporter (probably including aromatic amino acids as well as thr, met lys, glu and others), YddG. Its topology with 10 TMSs and both the N- and C-termini inside has been established (Airich et al. 2010). This system has been used for the export of tryptophan for commercial purposes (Wang et al. 2013). The 3-d structures (PD# 5I20) of a homologue (TC# 2.A.7.3.66) has been determined at 2.4 Å resolution, showing the outward facing conformation of a basket shaped structure with a central substrate binding cavity (Tsuchiya et al. 2016).

Heterodimeric SMR-like transporter with subunits of 144 and 151 aas and 4 TMSs each. The two encoding genes map adjacent to a LysR transcription factor and on the other side, to a RhtB homologue, that possibly exports serine, threonine, homoserine and/or homoserine lactones. Could function in the uptake of a quorum sensing acylhomoserine lactone.

Transporter of unknown function of 143 aas and 5 TMSs. Its gene maps near a thioredoxin domain-containing oxidoreductase that may act on glycine, sarcosine and/or betaine. Possibly the transporter acts on one of these substrates.

YnfA is a 108 aa E. coli protein with 4 established TMSs and both the N- and C-termini in the periplasm (Drew et al., 2002). Its homologues are found in a broad range of Gram-negative and Gram-positive bacteria as well as archaea and eukaryotes. The sizes of bacterial homologues range from 98 aas to 132 aas, with a few exceptions. Plant proteins can be as large as 197aas. The first two TMSs are homologous to the second two in these 4 TMS proteins. A Methanosarciniae mazei homologue of 94 aas and a Geobacillus kaustophilus homologue of 104 aas have only 2 TMSs with 30 residue extensions C- and N-terminal, respectively. No functional data are available for any of its homologues. This family is the YnfA UPF0060 family.

Csg2 (Cls2) Ca2+ homeostasis protein. Cells lacking Csg2p accumulate Ca2+ in a pool which is exchangeable with extracellular Ca2+ . The mutant cells are Ca2+ sensitive. The protein has 410 amino acyl residues, with 9-10 TMSs. It exhibits an EF-hand Ca2+ binding motif on the lumenal side of the endoplasmic reticular membrane. It is possible that it functions in Ca2+sequestration. It regulates the activities of CSH1 and SUR1 during mannosyl phosphorylinositol ceramid synthesis. It forms heterodimers with CSH1 and SUR1 (Beeler et al. 1994; Takita et al. 1995). Cls2p likely functions in releasing Ca2+ from the endoplasmic reticulum, somehow cooperating with calcineurin (Tanida et al. 1996). It regulates the transport and protein leves of the inositol phosphorlyceramide mannosyltransferases Csg1 and Csh1 (Uemura et al. 2007).

Prion-inhibition and propagation, HeLo domain of 901 aas. Contains a domain C-terminal to the transmembrane DMT domain that is homologous to that found in the family with TC# 1.C.104, the Heterokaryon Incompatibility Prion/Amyloid Protein (HET-s) Family.